This application is a 371 of PCT/FR99/03123 filed Dec. 14, 1999.
The present invention relates to a novel process for preparing (R)-(+)-3-{1-[2-(4-benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea and the salts, solvates and/or hydrates thereof.
(R)-(+)-3-{1-[2-(4-Benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea, of formula: 
referred to hereinbelow as compound A, is a novel powerful and selective non-peptide antagonist of the NK2 receptors of neurokinin A in various species, in particular of the human NK2 receptors (X. Emonds-Alt et al., Neuropeptides, 1997, 31 (5), 449-458) and, consequently, may be useful especially in the treatment of complaints of the respiratory, gastro-intestinal, urinary, immune or cardiovascular system and of the central nervous system, and also for pain and migraine.
The preparation of compound A is illustrated in international patent application WO 96/23787. According to said document, compound A is prepared by reacting (+)-4-benzoyl-2-(3,4-difluorophenyl)-2-[2-(methanesulfonyloxy)ethyl]morpholine (compound B) with 3-(4-phenylpiperid-4-yl)-1,1-dimethylurea para-toluenesulfonate (compound C), in the presence of potassium carbonate, followed by conversion to its hydrochloride. However, this process has disadvantages and drawbacks, which are sufficient to exclude it from any use on an industrial scale.
For example, compound A prepared by this process is obtained in a relatively low yield, of about 38% calculated on the basis of compound B, according to the description of patent application WO 96/23787.
The main reason for this low yield is the formation, during the reaction of compound B with compound C, of numerous impurities in the reaction medium, leading to a low yield for conversion to compound A. It has been possible to isolate and identify these impurities, the main one of which (compound D) has the formula: 
It has been found that the formation of these impurities, especially of compound D, is due to the instability of compound C in the form of the free base in solution. Thus, a stability study carried out on compound C at 50xc2x0 C. in acetonitrile shows that it rapidly decomposes (about 5% per hour) and gives a multitude of products corresponding to a polymerization (dimer, trimer, etc.), thus excluding the use of compound C on an industrial scale.
Furthermore, the presence of these impurities, in particular of compound D, in the reaction medium, makes it difficult to separate out and purify compound A.
Consequently, the search for a process to prepare compound A which does not have the drawbacks and disadvantages of the known prior art process remains of unquestionable interest.
A novel process for preparing compound A which uses stable starting materials and intermediate compounds in the operating conditions, and which does not lead to the formation of the impurities present during the prior art process, has now been found.
Thus, according to one of its aspects, a subject of the present invention is a process for preparing (R)-(+)-3-{1-[2-(4-benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea, and the salts, solvates and/or hydrates thereof, of formula: 
characterized in that:
(+)-4-benzoyl-2-(3,4-difluorophenyl)-2-(2-benzenesulfonyloxyethyl)morpholine of formula: 
xe2x80x83is reacted, in the presence of a base, with tert-butyl (4-phenylpiperid-4-yl)carbamate of formula: 
xe2x80x83to give tert-butyl (+)-(1-{2-[4-benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl]ethyl}-4-phenylpiperid-4-yl)carbamate, of formula 
xe2x80x83the compound of formula (V) thus obtained is deprotected by the action of an acid, to give (+)-[2-[2-(4-amino-4-phenylpiperid-1-yl)ethyl]2-(3,4-difluorophenyl)morpholin-4-yl]phenylmethanone, of formula 
c) the compound of formula (VI) thus obtained is reacted first with a reactive derivative of carbonic acid, in the presence or absence of base, and then with dimethylamine to give the expected compound of formula (I);
d) the compound of formula (I) thus obtained is optionally converted into a salt thereof with pharmaceutically acceptable mineral or organic acids.
In the process according to the invention, it is possible to combine two or more steps.
Thus, for example, steps a) and b) may be combined in order to give compound (VI) directly from the compound of formula (III). Similarly, steps c) and d) may be combined. It is also possible to combine all the steps of the process according to the invention, which means that all the steps are carried out without isolating the intermediate compounds of formulae (V) and (VI), thereby simplifying the process.
Salts of the compounds of formula (V) or (VI) and also of the compound of formula (I) may be formed. These salts comprise not only those with mineral or organic acids which allow a suitable separation or crystallization of the compounds of formula (V), (VI) or (I), but also those which form pharmaceutically acceptable salts with the compound of formula (I), such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methane sulfonate, methyl sulfate, maleate, fumarate, succinate, 2-naphthalenesulfonate, glyconate, gluconate, citrate, isethionate, benzenesulfonate or para-toluenesulfonate.
Compound A thus obtained may be subsequently separated from the reaction medium according to the conventional methods.
Compound A obtained is isolated in the form of the free base or of a salt thereof, for example the hydrochloride, the fumarate or the succinate. It is also possible to isolate, for example, compound A in the form of the fumarate and to convert it into another of its salts, first by neutralizing it then by treating the free base with an acid, for example succinic acid.
When compound A is obtained in the form of the free base, the salification is carried out by treatment with the chosen acid in an organic solvent. By treating the free base, dissolved, for example, in an ether such as diethyl ether or in an alcohol such as methanol, ethanol or 2-propanol, or in acetone, or in dichloromethane or in ethyl acetate, with a solution of the chosen acid in one of the abovementioned solvents, the corresponding salt is obtained, which is isolated according to the conventional techniques.
Thus, the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, benzenesulfonate, para-toluenesulfonate, oxalate, maleate, succinate, fumarate, 2-naphthalenesulfonate, glyconate, gluconate, citrate or isethionate is prepared, for example.
Preferably, the process according to the invention is used to prepare compound A in the form of the succinate or fumarate.
Thus, compound A in the form of the free base, dissolved in acetone, is treated at room temperature with succinic acid dissolved in acetone and the corresponding succinate is obtained, which is isolated according to the conventional techniques.
Similarly, compound A, in the form of the free base, dissolved in acetone, is treated under hot conditions with fumaric acid in acetone to give, after cooling to room temperature, the corresponding fumarate which is isolated according to the conventional techniques.
(R)-(+)-3-{1-[2-(4-Benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea succinate is novel and forms part of the invention.
(R)-(+)-3-{1-[2-(4-Benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea fumarate is novel and forms part of the invention.
When compound A is obtained in the form of a salt thereof, for example the hydrochloride or the fumarate, the free base may be prepared by neutralizing said salt with a mineral or organic base, such as sodium hydroxide or triethylamine, or with an alkali metal carbonate or bicarbonate, such as sodium or potassium carbonate or bicarbonate, according to the conventional methods.
When carrying out the process according to the invention, it is possible to obtain compound A or a salt thereof in a final yield of about 55% to 70% calculated relative to the starting compound of formula (III).
A subject of the present invention is thus a process for preparing (R)-(+)-3-{1-[2-(4-benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea, and the salts, solvates and/or hydrates thereof, of formula: 
characterized in that (+)-[2-[2-(4-amino-4-phenylpiperid-1-yl)ethyl]-2-(3,4-difluorophenyl)morpholin-4-yl]phenylmethanone, of formula: 
is reacted, in an inert solvent, first with a reactive derivative of carbonic acid in the presence or absence of base, and then with dimethylamine, and the compound of formula (I) thus obtained is optionally converted into a salt thereof with pharmaceutically acceptable mineral or organic acids.
Among the reactive derivatives of carbonic acid that are preferred are 1,1xe2x80x2-carbonyldiimidazole, phosgene and p-nitrophenyl chloroformate.
It is particularly preferred according to the invention to use 1,1xe2x80x2-carbonyldiimidazole.
The reactive derivative of carbonic acid is used in the reaction in a proportion of from 1 to 3 molar equivalents per molar equivalent of compound of formula (VI), preferably from 1 to 2 molar equivalents.
When 1,1xe2x80x2-carbonyldiimidazole is used, the reaction is carried out in the absence of base. When phosgene or p-nitrophenyl chloroformate is used, the reaction is carried out in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine; triethylamine is preferably used.
The base is used in the reaction in a proportion of from 1 to 6 molar equivalents per molar equivalent of reactive derivatives of carbonic acid.
The dimethylamine is used in the reaction in a proportion of from 1 to 6 molar equivalents per molar equivalent of compound of formula (VI) and preferably from 1 to 4 molar equivalents.
The inert solvent may be, for example, a C1-C4 haloaliphatic hydrocarbon such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride. Dichloromethane is a preferred solvent.
The inert solvent is used in a proportion of from 2 to 15 equivalents by volume per equivalent by weight of compound of formula (VI). The solvent is preferably used in a proportion of from 5 to 10 equivalents by volume per equivalent by weight of compound of formula (VI).
The reaction is carried out at a temperature of between xe2x88x9220xc2x0 C. and 25xc2x0 C.
The reaction thus described takes place over a period of from 4 to 15 hours.
The compound of formula (VI) and the salts thereof are novel and form part of the invention.
According to another of its aspects, a subject of the invention is a process for preparing (+)-[2-[2-(4-amino-4-phenylpiperid-1-yl)ethyl]-2-(3,4-difluorophenyl)morpholin-4-yl]phenylmethanone, or a salt thereof, of formula: 
characterized in that tert-butyl (+)-(1-{2-[4-benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl]ethyl}-4-phenylpiperid-4-yl)carbamate, of formula: 
is deprotected by the action of an acid, in an inert solvent, and the compound of formula (VI) thus obtained is optionally converted into a salt thereof.
A strong acid such as hydrochloric acid, trifluoroacetic acid or formic acid is preferably used to carry out the deprotection. The hydrochloric acid may be generated in situ from acetyl chloride and methanol.
It is particularly preferred to use hydrochloric acid.
The acid is used in the reaction in a proportion of from 4 to 10 molar equivalents per molar equivalent of compound of formula: (V) and preferably from 4 to 6 molar equivalents.
The inert solvent may be, for example, methyl isobutyl ketone, dichloromethane, ethyl acetate, toluene or a mixture of these solvents. Methyl isobutyl ketone is a preferred solvent.
The inert solvent is used in a proportion of from 2 to 15 equivalents by volume per equivalent by weight of compound of formula (V). The solvent is preferably used in a proportion of from 2 to 5 equivalents by volume per equivalent by weight of compound of formula (V).
The reaction is carried out at a temperature of between 10xc2x0 C. and 60xc2x0 C., preferably at a temperature of between 20xc2x0 C. and 40xc2x0 C.
The reaction takes place over a period of from 30 minutes to 18 hours.
Compound (VI) thus obtained may be subsequently separated from the reaction medium according to the conventional methods.
The compound of formula (VI) obtained is isolated in the form of the free base or of a salt thereof, by using the methods mentioned above for compound A.
The compound of formula (V) and the salts thereof are novel and form part of the invention.
According to another of its aspects, a subject of the invention is a process for preparing tert-butyl (+)-(1-{2-[4-benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl]ethyl}-4-phenylpiperid-4-yl)carbamate, or a salt thereof, of formula: 
characterized in that (+)-4-benzoyl-2-(3,4-difluorophenyl)-2-(2-benzenesulfonyloxyethyl)morpholine, of formula: 
is reacted with tert-butyl (4-phenylpiperid-4-yl)carbamate, of formula: 
in the presence of a base, in an inert solvent as a mixture with water, and the compound of formula (V) thus obtained is optionally converted into a salt thereof.
The compound of formula (IV) is used in the reaction in a proportion of from 1 to 1.25 molar equivalents per molar equivalent of compound of formula (III).
The base used in the reaction is chosen from an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or from alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate. Potassium carbonate is preferably used.
The base is used in the reaction in a proportion of from 1 to 3 molar equivalents per molar equivalent of compound of formula (III).
Water is used in the reaction in a proportion of from 1 to 3 equivalents by volume per equivalent by weight of base.
The inert solvent may be, for example, methyl isobutyl ketone, toluene, acetonitrile, ethanol or a mixture of these solvents. Methyl isobutyl ketone is a preferred solvent.
The inert solvent is used in a proportion of from 2 to 15 equivalents by volume per equivalent by weight of compound of formula (III). The solvent is preferably used in a proportion of from 2 to 5 equivalents by volume per equivalent by weight of compound of formula (III).
The reaction is carried out at a temperature of between 20xc2x0 C. and 90xc2x0 C.
The reaction takes place over a period of from 2 to 30 hours.
The compound of formula (V) thus obtained may be subsequently separated from the reaction medium according to the conventional methods.
The compound of formula (V) obtained is isolated in the form of the free base or of a salt thereof, using the methods mentioned above for compound A.
Alternatively, the compound of formula (VI) may also be prepared, in the process according to the invention, directly and in a single step starting with the compound of formula (III), thereby simplifying the process.
According to another of its aspects, a subject of the invention is another process for preparing (+)-[2-[2-(4-amino-4-phenylpiperid-1-yl)ethyl]-2-(3,4-difluorophenyl)morpholin-4-yl]phenylmethanone, or a salt thereof, of formula: 
characterized in that (+)-4-benzoyl-2-(3,4-difluorophenyl)-2-(2-benzenesulfonyloxyethyl)morpholine of formula: 
is reacted with 4-amino-4-phenylpiperidine of formula: 
in the presence of a base, in an inert solvent as a mixture with water, and the compound of formula (VI) thus obtained is optionally converted into a salt thereof.
The compound of formula (IX) is used in the reaction in a proportion of from 1 to 1.25 molar equivalents per molar equivalent of compound of formula (III).
The base used in the reaction is chosen from an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or from alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate. Potassium carbonate is preferably used.
The base is used in the reaction in a proportion of from 1 to 3 molar equivalents per molar equivalent of compound of formula (III).
Water is used in the reaction in a proportion of from 1 to 3 equivalents by volume per equivalent by weight of base.
The inert solvent may be, for example, methyl isobutyl ketone, toluene, acetonitrile, ethanol or a mixture of these solvents. Methyl isobutyl ketone is a preferred solvent.
The inert solvent is used in a proportion of from 2 to 15 equivalents by volume per equivalent by weight of compound of formula (III). The solvent is preferably used in a proportion of from 2 to 5 equivalents by volume per equivalent by weight of compound of formula (III).
The reaction is carried out at a temperature of between 20xc2x0 C. and 90xc2x0 C.
The reaction takes place over a period of from 2 to 30 hours.
The compound of formula (VI) thus obtained may be subsequently separated from the reaction medium according to the conventional methods.
The compound of formula (VI) obtained is isolated in the form of the free base or a salt thereof, using the methods described above for compound A.
The compound of formula (IV) is known and is prepared according to known methods such as those disclosed in EP-A-0 673 928.
The compound of formula (IX) is known and is prepared according to known methods such as those disclosed in WO 97/10211, in particular by deprotection, according to the conventional methods, of the known 4-amino-1-benzyl-4-phenylpiperidine prepared according to WO 97/10211 or WO 96/23787.
The compound of formula (III) is novel and forms part of the invention.
The compound of formula (III) is prepared according to the known methods such as those disclosed in WO 96/23787.
In particular, the compound of formula (III) is prepared according to the Scheme below. 
In step i), the compound of formula (VII) is reacted with benzoyl chloride, in the presence of a base such as sodium hydroxide, in an inert solvent such as dichloromethane or toluene as a mixture with water and at a temperature of between 10xc2x0 C. and 35xc2x0 C. After extraction and washing with water, the compound of formula (VIII) dissolved in the organic phase is reacted (step ii)) with benzenesulfonyl chloride, in the presence of a phase-transfer catalyst such as benzyltriethylammonium chloride, a base such as sodium hydroxide and water and at a temperature of between room temperature and 55xc2x0 C. After hydrolysis with water, the compound of formula (III) is isolated according to the conventional methods.
The compound of formula (III) may be reacted without being isolated from the medium in which it was produced. The compound of formula (VII) is known and is prepared according to known methods, such as those disclosed in WO 96/23787 or, specifically, in Tetrahedron : Asymmetry, 1998 9, 3251-3262.